2-halo-delta2 androsten derivatives and process



nite States 3,055,916 2-HAL0-A ANDROSTEN DERIVATIVES AND PROCESS AlbertBowers, John Edwards, and James C. Orr, Mexico City, Mexico, assignors,by mesne assignments, to Syntex Corporation, a corporation of Panama NoDrawing. Filed Oct. 20, 1961, Ser. No. 146,454 26 Claims. (Cl. 260-3973)The present invention relates to novel cyclopentanophenanthrenederivatives and to a process for the production thereof.

More particularly the present invention relates to 2- halo-A -androstenderivatives.

The novel compounds of the present invention are represented by thefollowing formulas:

In the above formulas X represents fluorine, chlorine or bromine; Rrepresents hydrogen or methyl; R represents hydrogen or a hydrocarboncarboxylic acyl group of less than 12 carbon atoms; R representshydrogen or a lower alkyl, alkenyl or alkinyl group such as for examplemethyl, ethyl, propyl, butyl, vinyl, propenyl, butenyl, ethinyl,propargyl and butinyl.

The compounds represented by the above formulas are anabolic-androgenicagents with a favorable'anabolic to androgenic ratio. They also areanti-estrogenic, antigonadotrophic, anti-fibrillatory and centralnervous system depressant compounds. In addition they lower the bloodcholesterol level, relieve pre-menstrual tensions and suppress theoutput of the pituitary gland.

The compounds represented by the above formula A wherein R is a loweralkenyl or alkinyl group are also progestational agents with high oralactivity. They also are anti-estrogenic, lower the blood cholesterollevel and have anti-aldosterone activity.

Some novel important intermediates in the production of the finalproducts mentioned above are 2,2-difluoroandrostan 17,6 ol-3-one,2,2-difiuoro-l9-nor-androstan- 17B ol-3-one,2,2-difluoro-19-nor-androstan-3B,17B-diol and2,2-difluoro-androstan-3fi, l7fi-diol.

The novel Z-flUOIO-170t-Ul1SllbStItll 6d compounds of the presentinvention are prepared by the process exemplified by the followingequation:

OH R W3 In the above Example R has the same meaning as previously setforth.

In practicing the process just outlined, the starting compound which is2a-fiuoro-androstan-17B-ol-3-one or the 19'-nor derivative thereof (I),is treated with pyrrolidine in a suitable solvent such as benzene thusfurnishing the corresponding 3-pyrrolidino-2-fluor0-A +androsten-17 8-01compound which upon reaction with perchloryl fluoride in a suitablesolvent, preferably benzene, affords the corresponding2,2-difluoro-androstan-l7B-al-3-one derivative (II). t

Reduction of the last named compound preferably with sodium borohydridefurnishes the corresponding 2,2-difluoro-androstane-3,B,l7fi-diolcompound (III) which upon treatment with a suitable agent such aschromous chloride solution or zinc in ethanol furnishes the respective2- fluoro-A -androsten-17,8-01 (IV). Oxidation of this compound with anoxidizing agent such as chromium trioxide in pyridine furnishes the2-fluoro-A -androsten-l7-one or the 19-nor-derivative thereof (V).

The novel 2-bromo-17a-unsubstituted compounds of the present inventionare prepared by the process illustrated by the following equation:

V III XII responding 2m-brorno-3-keto derivative (VII). Treatment ofthis compound with isopropenyl acetate in the presence ofp-toluenesulfonic acid at reflux temperature furnishes the respective2-bromo-3,l7p-diacetoxy-A -androstene derivative (VIII). Bromination ofthis compound with bromine in a suitably buffered solution, preferablyan acetic acid-carbontetrachloride-sodium acetate mixture, affords thecorresponding 2,2-dibromo-l7/3- acetoxy-androstan-3-one (IX), which uponreduction with a suitable agent, such as sodium borohydride in amoisture containing solution, furnishes the respective2,2-dibromo-androstane-Zifi,1713-dio1 (X).

Treatment of this latter compound with a suitable agent such as achromous chloride solution or Zinc in ethanol gives the 2-bromo-A-androsten-175-01 or the l9-nor derivative thereof (XI), which uponoxidation with, for example, chromium trioxide in pyridine, yield thecorresponding 17-ketone (XII).

The 2-chloro-17u-unsubstituted compounds of the present invention may beprepared by the process exemplified by the following equation:

b m 0= p, 01 l b .d W Q In the above formulas R has the same meaning asheretofore set forth.

In practicing the above outlined process, the starting compound which isandrostan-17B-ol-2-one acetate or the l9-nor derivative thereof (XIII)is treated with phosphorus pentachloride in an inert solvent such ascarbon tetrachloride at reflux temperature for a period of time of theorder of 2 hours, thus affording the corresponding 2-chloro-A -androsten17;? ol l7 acetate (XIV). Conventional saponification of this compoundfurnishes the free 17,8-alcohol (XV) which upon oxidation affords thecorresponding 2-chloro-A -androsten-17- one.

The 2-halo-17a-substituted compounds of the present invention areprepared by the process illustrated by the following equation:

,A A l In the above formulas X, R and R have the same meaning aspreviously set forth.

In practicing the process just outlined, the starting 2- halo-A-androsten-l7-one compound (XVII) is treated with an alkinyl, alkenyl oralkyl magnesium halide as for example methyl magnesium promide, vinylmagnesium bromide or ethynyl magnesium bromide, thus furnishing thecorresponding 17a-alkyl, alkenyl or alkynyl derivatives (XVIII).

The heretofore described secondary alcohols (IV, XI, XV) areconventionally acylated in pyridine with an acylating agent, as forexample acetic anhydride or caproic anhydride affording thecorresponding acylates.

The tertiary alcohols (XVIII) are conventionally acylated in thepresence of p-toluenesulfonic acid with an excess of an acylating agent,as for example an anhydride of a hydrocarbon carboxylic acid of the typedescribed hereinabove, thus furnishing the corresponding l7fi-acyloxycompounds.

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention:

Example I A mixture of 3 g. of 2a-fluoro-androstan-17,6-ol-3-one.[Edwards and Ringold, J. Am. Chem. Soc. 81, 5262, 1959)], 50 cc. ofthiophene-free benzene and 4 mol equivalents of pyrrolidine was refluxedwith a water separator until no more water separated. The resultingmixture was evaporated to dryness and the residue recrystallized fromchloroform-methanol affording 3-pyrrolidino-2-fluoro-A-androsten-il7,8-01.

3 g. of the above pyrrolidino compound were dissolved in 900 ml. of drythiophene-free benzene and perchloryl fluoride was bubbled into thesolution for 1 minute. After Washing successively with saturated sodiumbicarbonate solution and Water, the benzene solution was dried andevaporated to dryness under reduced pressure. The residue was taken upin 100 ml. of a 1:1 mixture of benzene and petroleum ether. Thissolution was filtered through 10 g. of Florisil and the filtrateevaporated to dryness in vacuo. Recrystallization of the residue fromacetone-hexane afiorded 2,2-difluoro-androstan-17(3- ol-3-one.

Following the same procedure, there was treated2afiuoro-l9-nor-androstan-l7p ol-3-onep [prepared by the general methoddescribed by Edwards and Ringold, I. Am. Chem. Soc. 81, 5262, (1959)],furnishing 2,2-difluoro-19-nor-androstan-17/i-ol-3-one.

Example II A solution of 2 g. of sodium borohydride in 30 cc. ofmethanol was added with stirring to a solution of 2 g. of2,2difiuoro-androstan-17p-ol-3-one in 40 cc. of tetrahydrofuran. Themixture was kept at room temperature overnight, the excess reagent wasdecomposed by addition of acetic acid, the resulting solutionconcentrated to small volume in vacuo and diluted with water. Theproduct was extracted with ethyl acetate, the extract washed with water,dried and evaporated. Crystallization of the solid from acetone-hexanegave 2,2-difiuoroandrostane-3-17fi-diol.

When applying this procedure to2,2-difiuro-19-norandrostan-l7B-ol-3-one, there was obtained2,2-difluoro- 19-nor-androstan-3/3,17,8-diol.

Example III To a solution of 1 g. of 2,2-difluoro-androstane-3fi,17,8-diol in 200 cc. of acetone at room temperature, there was added 60 cc.of freshly prepared chromous chloride solution. The reaction wasvirtually instantaneous. The acetone was then removed under reducedpressure, water was added and the precipitate filtered oif and dried.Recrystallization from acetone-hexane yielded 2-fluoroAandrosten-17B-ol.

A mix-ture of 1 g. of 2,2-difluoro-androstane-3p,17B- diol, 2 g. of zincand 50 cc. of ethanol was refluxed for 1 hour. The mixture was thenfiltered through celite and the filtrate evaporated to dryness.Crystallization of the residue from acetone-hexane yielded 2-fluoro-A-androsten-17B-ol.

Following a second technique,2,2-difluoro-l9-nor-androstane-3B,l7fi-diol was treated by the sameprocedures afiording 2-fluoro-19-nor-A -and1'osten-17fl-o1 in eachinstance.

Example I V A solution of 6 g. of 2-fluoro-A androsten-1718-01 obtainedaccording to Example IH, in 120 cc. ofi pyridine was added to a mixtureof 6 g. of chromic trioxide in 120 cc. of pyridine. The reaction mixturewas kept at room temperature overnight. It was then diluted with ethylacetate, filtered through celite and the filtrate washed well withwater, dried and evaporated to dryness. Crystallization fromacetone-hexane afforded Z-fluoro- A -androsten-17-one.

. 6 When applying the above procedure to 2-fluoro-19- nor-A-androsten-flp-ol, there was obtained 2-fluoro-l9- nor-A-androsten-17-one.

Example V A solution of 5 g. of androstan-17B-ol-3-one in cc. of aceticacid was treated with a few drops of hydrogen bromide in acetic acid andsubsequently dropwise and with stirring with a solution of 1.1 molarequivalents of bromine in 50 cc. of acetic acid. After all the brominehad been consumed, water was added, and the formed precipitate filtered,washed with water to neutral and dried under vacuum. Recrystallizationfrom acetonehexane yielded 2a-bromo-androstan-17/3-ol-3-one.

19-nor-androstan-l7fl-ol-3-one was treated following the aboveprocedure, thus afiording 2oc-br0II10-19-I10I- androstan-l7/3-ol-3-one.

Example VI A mixture of 1.2 g. of 2a-bromo androstan-17,8-01-3- one, 20cc. of isopropenyl acetate and 60 mg. of paratoluenesulfonic acid wasrefluxed using an air condenser so that approximately 2 cc. of solventdistilled oil over a period of 30 minutes.

A water-cooled condenser wa then substituted for the air con-denser andrefluxing continued for 24 hours.

The cooled solution was diluted with ethyl acetate, Washed with water,aqueous sodium bicarbonate, and then with water until neutral.

The organic solution was dried with sodium sulfate, evaporated todryness, and the product crystallized from methylene chloride-hexane,thus furnishing 2-bromo-3, 17/3-diacetoxy-A -androstene.

Upon treatment of 2a-bromo-l9-nor-androstan-17fi-o1- 3-one by the aboveprocedure, there was obtained 2- brorno-3 17,8-diacetoxy-19-nor-A-androstene.

Example VII The solvent for this reaction is composed of 80 cc. ofglacial acetic acid, 20 cc. of carbon tetrachloride and 1 g. of sodiumacetate.

A stirred solution of 2.5 g. of 2-bromo-3,17fi-diacetoxy-A -androstenein 200 cc. of the solvent is treated dropwise in the course of 30minutes at room temperature with a solution of 1.05 molar equivalents ofbro mine in solution of 20 cc. of the above solvent. It was then pouredinto water, extracted with methylene chloride and crystallized, thusyielding 2,2-dibromo-androstan-17/3-ol-3-one-l7-acetate.

When applying the above technique to 2-bromo-3,-l7fidiacetoxy-l9-nor-A-androstene, there was obtained 2,2- dibromo-19-nor-androstan-l7B-ol-3one-17-acetate.

Example VIII A solution of 1 g. of sodium borohydride in 3 cc. of waterwas added to an ice-cooled solution of 1 g. of 2,2-dibromo-androstan-l7lB-o1-3-one l7-acetate in cc. of methanol and themixture was allowed to stand for 16 hours at room temperature. Theexcess reagent was decomposed by addition of acetic acid, the solutionconcentrated to small volume in vacuo and diluted with water. Theproduct was extracted with ethyl acetate, the extract was washed withwater, dried and evaporated. The solid residue was purified bycrystallization from acetonehexane to give the2,2-dibromo-andros-tane-3/8,17,8-diol.

2,2-dibromo-19-nor-androstan-17B-ol-3-one-17 acetate was treated by thesame technique furnishing 2,2-d-ibromo-19-nor-androstane-3,B-IZB-diol.

Example IX 'tively Z-bromo-M-androsten-17,8-01 and 2-bro1no-l9- 7Example X The two last named compounds were oxidized following theprocedure described in Example IV, furnishing correspondingly 2-bromo-A-androsten-l7-one and 2- bromo-l9-nor-A -androsteu-l7-one.

Example Xl A mixture of 4 g. of androstan-17fi-ol-2-one acetate(obtained in accordance with copending US. Patent Application Serial No.128,362 filed August 1, 1961), 6 g. of phosphorus pentachloride and 60cc. of carbon tetrachloride was refluxed for 2 hours in the absence ofmoisture. It was then cautiously poured into water. The organic layerwas washed several times with water, dried over sodium sulfate andevaporated to dryness furnishing Z-chloro-M-androsten-175-01 acetate.

Example XII l9-nor-androstan-17/3-ol-2-one acetate was obtainedfollowing the process described in copending application Serial No.128,362 for the production of androstan-l7fiol-2-one acetate:

The starting compound which is the dihydro-19-norallotestosterone wasborminated in the presence of hydrogen bromide givingZa-bromo-l9-nor-androstan-175-01-3- one. Reduction of this compound withsodium borohydride yielded 2a-bromo-l9-nor-androstane-3/3,l7f3-diolwhich on treatment with zinc in acetic acid at reflux temperatureafforded 19-nor-A -androsten-17 6-01. Conventinal acetylation of thiscompound furnished the 19-nor- A -androsten-l7/3-ol-l7-acetate.Treatment of the last named compound with N-bromoacetamide in dioxaneand in the presence of perchloric acid afforded 3a-bromo-l9-nor-androstane-Zfi,17fi-diol-l7-acetate.

This last compound was oxidized with chromium trioxide in pyridine andfurnished 3oz-b1'OH10-19-I1OI-21Ildl0- stan-17fl-ol-2-one-17-acetatewhich upon treatment with zinc in acetic acid gave19-nor-androstan-l7f3-ol-2-one-l7- acetate. Conventional saponificationof the last named steroid afiorded l9-nor-androstan-17/3-ol-2-one whichupon conventional acetylation gave l9-nor-androstan-17fiol-2-oneacetate.

This latter compound Was treated following the procedure described inExample XI, thus furnishing 2- chloro-19-nor-A-androsten-17p-ol-acetate.

Example XIII A solution of 3 g. of 2-ch1oro-A -androsten-175-01- acetatein 150 cc. of methanol was refluxed for 1 hour with 3 g. of potassiumcarbonate in 6 cc. of water. It was then cooled and poured into water.The formed precipitate was collected, dried and recrystallized fromacetone-hexane to yield Z-chloro-M-androsten-17/3-01.

Z-chloro-l9-nor-A -androsten-17p-ol-acetate was treated by the sametechnique yielding 2-ch1oro-19-nor-A -androsten-17fi-ol.

Example XIV 2-chloro-A -androsten-l7p-ol and 2-ch1oro-l9-nor-Aandrosten-17fl-ol were oxidized by the method described in Example IVaffording respectively 2-chloro-A -androsten-17-oue and2-chloro-l9-nor-A -androsten-l7-one.

Example XV A solution of g. of 2-fluoro-A -androsten-17-one in 250 cc.of thiophene-free benzene was treated with 27.5 cc. of 4 Nmethylmagnesium bromide in ether, and the mixture refluxed with theexclusion of moisture for 3 hours. The cooled mixture was cautiouslytreated with excess aqueous ammonium chloride solution and the productisolated by ethyl acetate extraction. The extract was wased with Water,dried over anhydrous sodium sulfate and evaporated to dryness.

Recrystallization from methylene chloride-hexane afforded2-fluoro-17a-methyl-A -androsten-17,8-01.

Following the above procedure, there were treated the starting compoundslisted below with the indicated akyl, alkenyl or alkinyl magnesiumbromide affording the corresponding products, hereinafter set forth:

2-iiuor0-19-n0r-M- audrosten-l7-one.

methyl magnesium bromide.

Do vinyl magnesium bromide. nor-A -androsten- 176-01. Do ethynylmagnesium afluoro-lh-ethynylbromide. l -nor-A -androsten- 17fl-0l.2-chloro-A -androstenmethyl magnesium 2-ehloro-17a-rnethy1- 17-one.bromide. A -andr0sten-17B-01. D0 vinyl magnesium Z-ehloro-lh-vinyi-Abromide. androsten-17B-ol. Do ethynyl magnesiumQwhloro-lh-ethynylbromide. A -andr0sten-17fl-01. 2-chl0r0-19-n0r-Amethyl magnesium 2-ch10ro-1 7a-methylandrosten-l7-0ne. bromide. lggiof-A-androsten- -0 D0 vinyl magnesium 2-Chl0IO-17a-Vl1'1Y1-19- bromide.nor-A -uudrosten- 17 3-01. Do ethynyl magnesium 2-chl0ro-17e-ethyny1-bromide. IQ-nor-A -androsteu- 17 3-01. z-bromo-A -androstenmethylmagnesium 2-bromo-17e-methy1- 17-one. bromide. A -androsten-l7B-0l.

Do rvinyl magnesium 2-br0rn0-17a-vinyl-A bromide. audrosten-17B-ol.ethynyl magnesium 2-bl'0l110-17a-OthyIlYlbromide. N-androston-l 75-01.2-brom0-19-nor-A methyl magnesium 2-br0m0-17e-n1ethy1- androsten-l7-0ne.bromide. lgglolr-A -androsten- -O Do vinyl magnesium 2-brom0-17e-viny1-bromide. lQ-nor-N-androsten- -01. Do ethynyl magnesium2-bromo-17e-ethyny1- bromide. 19-nor-A -androsten- Example XVI A mixtureof 1 g. of 2-fluor0-A -androsten-175-01, 4 cc. of pyridine and 2 cc. ofacetic anhydride was kept at room temperature overnight, poured into icewater and the formed precipitate was filtered, washed with Water anddried. Crystallization from acetone-hexane gave the 17- acetate of2-fluoro-A -androsten-17 8-01.

When applying the above technique to 2-fluoro-l9-nor- A-androsten-l7B-ol, 2-chloro-A -androsten-17fl ol, 2- chloro-19-nor-A-andr0sten-1713-01, 2-bromo-A -androsten- 17(3-01, and 2-bromo-19-nor-A-androsten-1713-01, there were obtained 2-fluoro-19-nor-A-androsten-17p-o1-acetate, 2-chloro-A -androsten-17fl-ol-acetate,2-chloro-19-nor-A androsten-l7l8-ol acetate, 2-bromo-A-androsten-175-01- acetate, and 2-bromo-l9-nor-A-androsten-17fi-ol-acetate.

Example XVII Following the technique of the foregoing example, butsubstituting acetic anhydride by propionic anhydride, caproic anhydride,cyclopentylpropionic anhydride and benzoyl chloride, there werecorrespondingly obtained the propionates, caproates,cyclopentylpropionates, and benzoates of the named starting compounds.

Example XVIII A mixture of 1 g. 2-fluoro-l7a-methyl-A -androsten- 173-01, 1 g. of p-toluenesulfonic acid monohydrate, 50 cc. of acetic acidand 25 cc. of acetic anhydride was kept at room temperature for 24hours. It was then poured into water and stirred until the excess ofanhydride had hydrolyzed. Isolation of the product by methylene chlorideextraction and crystallization of the residue from acetone ether gave2-fluoro-17a-methyl-A -androsten-17pol-17-acetate.

The starting compounds listed below were treated by the above describedtechnique furnishing the corresponding products set forth hereinafter:

Starting compounds Products 2-chloro-17a-ethyny1-19-nor-Aaudrosten-17B-ol.

2-brompAhmethyl-N-androsten- 2-bromo-17a-vinyl-A -androsten-2-bromodhcthynyl-N-androsten- Example XIX We claim:

1. A compound of the following formula:

wherein X is a member of the group consisting of fluorine,

chlorin and bromine; R is selected from the group consisting of hydrogenand methyl; R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl and lower alkinyl. 2-fluoro-A -androsten--01. 2-fluoro-19-nor-A-androsten-17 8-01. 2-chloro-A androsten-175-01. 2-chloro-19-nor-A-andr0sten-17fi-ol. 2-bromo-A -androsten-17,8-01. 2-brorno-19-nor-A=androsten-17,8-01. Z-fiuoro-l7a-methyl-A =androsten-175-01.Z-fluoro-l7a-methyl-19-nor-A -androsten-17 8-01.

2-fluoro-l7oa-vinyl-A -androsten-175-01. Z-fluoro-l7a-vinyl-l9-nor-A-androsten-175-01. Z-fluoro-l7oc-ethyny1-A -androsten-17,8-01.Z-fluoro-l7a-ethynyl-19-n0r-A -androsten-17,8-01. 2-chloro-17a-methyl-A-androsten-17 6-01. 15. 2-c-hloro-l7a-vinyl-l9-nor-A -androsten175-01.16. 2-chloro-17u-ethynyl-l9-nor-A -androsten-175-01. 17.2-bromo-17oc-methy1-A -androsten-17 3ol. 18. Z-bromo-17a-vinyl-19-nor-A-androsten-1713-01. l9. 2-bromo-17a-ethynyl19nor-A -androsten-175-01.20. A process for the production of 2-chloro-A androstene derivativeswhich comprises treating the corresponding androstan-Z-one withphosphorus pentachloride in a suitable solvent.

21. The process of claim 20 wherein the solvent is carbon tetrachloride.

22. A compound of the following formula:

wherein X is a member of the group consisting of fluorine, chlorine, andbromine and 'R is selected from the group consisting of hydrogen andmethyl.

'24. 2,2-difluoro-19-nor-androstan17/3-ol-3-one.

26. 2,2-difluoro-androstane-3/3,l7B-diol.

No references cited.

1. A COMPOUND OF THE FORMULA: